Drug dispersion degree and drug dissolution rate in Hybrane S1200-based instant-release matricial particles prepared by hot melt extrusion.

The objective of this study is to evaluate the dissolution of a poorly soluble drug (prednisolone) from different sized matricial particles (from <250 to >1500 µm) with two drug contents (10% or 20%) obtained by hot melt extrusion using the hyperbranched polyesteramide Hybrane S1200 (water-soluble and with a Tg of 45 °C) as the carrier. X-ray diffraction, differential scanning calorimetry and SEM studies permit us to conclude that in 10% prednisolone extrudate, the drug is mainly dispersed within the carrier, whereas in those containing 20% an important fraction of the drug remains in a crystalline state and is accumulated on the surface of the extrudates. On particles proceeding from 10% drug extrudate, the drug dissolution rate is very high and slightly dependant on particle size and in all cases, higher than the pure micronized drug. However, on particles proceeding from 20% prednisolone extrudate particle size have a major effect on drug dissolution rate, attributable to higher proportions of crystalline drug accumulated on the surface, hindering polymer dissolution. Thus, the reduction of the particle size after extrudate grinding creates new surfaces from inside, that leads to strong increments on prednisolone dissolution rate, and becomes higher than the pure micronized drug one when the particle size is <250 µm.

Compression behavior of formulations from Phyllanthus niruri spray dried extract.

The aim of this study was to evaluate the compression behavior of Phyllanthus niruri spray dried extract as well as the influence of excipients on the properties of tablets containing a high dose (70% by weight) of this product. The effect of excipients was studied by a 22 factorial design. The factors investigated were the type of disintegrant (croscarmellose sodium and sodium starch glycolate) and the type of filler/binder (microcrystalline cellulose and dibasic dicalcium phosphate). The tablets were produced on a single punch tablet press using a constant compression force of 5000 N. The tablets formulated with microcrystalline cellulose presented a plastic behavior while the tablets containing dibasic dicalcium phosphate disclosed a fragmentary behavior. The disintegration time was significantly influenced by both factors, however, the tensile strength was only affected by the filler/binder. Additional experiments considering the influence of the compression force (2500 N and 5000 N) and the proportion of croscarmellose sodium (1.5%, 3.0% and 6.0%) on the mechanical properties of the tablets were performed by a 2 x 3 factorial design. Both factors significantly affected the tensile strength, friability and disintegration time of the tablets.

The synergistic effect of VEGF and biomorphic silicon carbides topography on in vivo angiogenesis and human bone marrow derived mesenchymal stem cell differentiation.

Topographical features of biomaterials are able to modulate cell attachment, spreading and differentiation. The addition of growth factors to implantable biomaterials can modify these cellular responses, enhancing their therapeutic potential. The aim of this research is to establish the influence of biomorphic silicon carbide ceramics (bioSiCs) surface topography on the proliferation and osteoblastic differentiation of mesenchymal stem cells and the potential synergistic effect of the ceramic porous structure together with vascular endothelial growth factor loading (VEGF) on the surface mediated osteoblastic differentiation. Three porous bioSiCs with important differences in their microstructure were obtained from different natural precursors. Samples loaded with or without VEGF through ionic interactions were cultured with human umbilical vein endothelial cells (HUVEC) or bone marrow derived mesenchymal stem cells (hMSCs). Cell behaviour and protein activity with regard to bioSiC porous structure and surface properties were analysed. An in vivo model (Chick Chorioallantoic Membrane; CAM) was used to assess the capability of the VEGF loaded systems to promote angiogenesis. Experimental data show that loaded systems were able to control the release of VEGF for up to 15 d ensuring the activity of the protein, increasing the proliferation of HUVECs and the formation of new blood vessels in the CAM. It was found that the selection of bioSiCs with a higher pore size promoted a higher concentration of osteoblastic differentiation markers of MSCs cultured on the surface of bioSiCs. Furthermore, the addition of VEGF to the systems was able to promote a faster osteoblastic differentiation according to the qPCR results, suggesting a synergy between both the surface properties and the controlled release of the growth factor. The VEGF loaded sapelli bioSiC was found to be the most promising material for bone tissue engineering applications.

EMF radiation at 2450 MHz triggers changes in the morphology and expression of heat shock proteins and glucocorticoid receptors in rat thymus.

AIMS: Electromagnetic fields (EMFs) can act as inducers or mediators of stress response through the production of heat shock proteins (HSPs) that modulate immune response and thymus functions. In this study, we analyzed cellular stress levels in rat thymus after exposure of the rats to a 2.45 GHz radio frequency (RF) using an experimental diathermic model in a Gigahertz Transverse Electromagnetic (GTEM) chamber. MAIN METHODS: In this experiment, we used H&E staining, the ELISA test and immunohistochemistry to examine Hsp70 and Hsp90 expression in the thymus and glucocorticoid receptors (GR) of 64 female Sprague­Dawley rats exposed individually to 2.45 GHz (at 0, 1.5, 3.0 or 12.0 W power). The 1 g averaged peak and mean SAR values in the thymus and whole body of each rat to ensure that sub-thermal levels of radiation were being reached. KEY FINDINGS: The thymus tissue presented several morphological changes, including increased distribution of blood vessels along with the appearance of red blood cells and hemorrhagic reticuloepithelial cells. Levels of Hsp90 decreased in the thymus when animals were exposed to the highest power level (12 W), but only one group did not show recovery after 24 h. Hsp70 presented no significant modifications in any of the groups. The glucocorticoid receptors presented greater immunomarking on the thymic cortex in exposed animals. SIGNIFICANCE: Our results indicate that non-ionizing sub-thermal radiation causes changes in the endothelial permeability and vascularization of the thymus, and is a tissue-modulating agent for Hsp90 and GR.

The adsorption of cellulose ethers in aqueous suspensions of pyrantel pamoate: effects on zeta potential and stability.

This work examined the physico-chemical phenomena induced in aqueous suspensions of pyrantel pamoate by two varieties of hydroxypropylmethylcellulose (HPMC) and sodium carboxymethylcellulose (NaCMC) of different molecular weights, and the effects of these phenomena on the physical stability of the suspension. The mechanism of the interfacial adsorption of the polymer was investigated by constructing adsorption isotherms: for the two HPMC varieties, the isotherms were of type L and were fitted with the Langmuir model; of the NaCMCs, only the variety with higher molecular weight was adsorbed, its adsorption isotherm being of type S (sigmoidal). The resulting monolayer films were characterized viscosimetrically, determining their thickness and the number of polymer molecules adsorbed per unit area. The nonionic polymers formed thinner, more continuous monolayers than the NaCMC. Only the nonionic polymers significantly altered the zeta potential of the systems. In the range of conditions studied, all the polymers stabilized the initially flocculated systems, decreasing sedimentation volume and increasing the time necessary to redisperse them (the redispersability value). This stabilization occurred either by the steric mechanism (HPMCs and the high-molecular-weight NaCMC) or by depletion mechanisms (low-molecular-weight NaCMC). Owing to the complexity of these mechanisms, sedimentation volume was not found to be a useful index of the consistency of the sediments obtained from the suspensions.

Interactions between hydroxypropylcelluloses and vapour/liquid water.

Understanding of the uptake of water vapour or liquid water by cellulose-based polymers is important because of the influence of these processes on many of the biologically or technologically relevant properties of these polymers. In this work we studied these processes in the cases of twelve hydroxypropylcelluloses with low or medium-high degrees of substitution (L-HPCs and HPCs, respectively), characterization of which showed significant differences in structural and physical parameters (substitution pattern, crystallinity, particle size, specific surface area, and intraparticular porosity). Water vapour sorption-desorption isotherms determined to characterize the uptake of water vapour were fitted well by the Young-Nelson model, the optimized parameters of which indicated that at all relative humidities the capacity to bind water vapour as a surface monolayer is greater for HPCs than L-HPCs, but the capacity to absorb water vapour internally is greater for L-HPCs than HPCs. Guggenheim-Anderson-deBoer (GAB) models fitted the sorption-desorption isotherms less well. Differential scanning calorimetry (DSC) experiments showed all sorbed water vapour to be held as non-freezing water. Isoperibol microcalorimetry experiments carried out to investigate interactions with liquid water showed enthalpies of hydration/dissolution of between -62.86 and -71.35 J g(-1) for L-HPCs and between -82.95 and -99.80 J g(-1) for HPCs, and DSC showed average numbers of non-freezing water molecules per polymer repeat unit of 2.65-4.19 for L-HPCs and 18.10-22.42 for HPCs. DSC characterization of the kinetics of the water uptake by 10 mg compacts obtained by direct compression of hydroxypropylcelluloses showed faster uptake by L-HPC compacts than by HPC compacts, among which there were significant differences in capacity for diffusive uptake. The explanations of the above differences in terms of the different substituent contents, particle sizes and porosities of the HPCs is supported by multiple linear regression analyses.

Glass transitions and viscoelastic properties of carbopol and noveon compacts.

Glass transitions of five varieties of Carbopol (acrylic acid polymers cross-linked with allyl sucrose or allyl pentaerythritol) and two varieties of Noveon (calcium salts of acrylic acid polymer cross-linked with divinylglycol) differing in cross-linking density and nature and content in residual solvents, were analysed (as compressed probes) by differential scanning calorimetry (DSC), modulated temperature differential scanning calorimetry (MTDSC), and oscillatory rheometry. All carbopol compacts showed a main glass transition, at a temperature between 130 and 140 degrees C, Tg, independently of their cross-linking degree and molecular weight. Additionally two batches of Carbopol 971P, which had greater contents in residual solvents, also presented a secondary transition at 65-70 degrees C. Sorption of water during storage of carbopol compacts at different relative humidity environments caused the Tg to strongly decrease. Compacts stored at 97.5% relative humidity have Tg below 0 degrees C and behave, at room temperature, as flexible hydrogels. The Gordon-Taylor/Kelley-Bueche equation only fit the dependence of Tg on water content well for carbopol compacts containing less than 15% water. The plasticizing effect of water was clearly evidenced in the considerable decrease in the storage and loss moduli of the compacts. Although the energy associated to the glass transitions of carbopol polymers, 0.40-0.50 Jg(-1) degrees C(-1), is high enough to be clearly detected by DSC, in some cases the evaporation of residual solvents may make it difficult to observe the Tg. This inconvenience is overcome using MTDSC or oscillatory rheometry. The decrease in Tg of carbopol caused by water sorption when compacts were stored at 97.5% R.H. explains why their loss (G") and storage (G') moduli at room temperature decreased four orders of magnitude. In contrast, in noveon varieties, calcium ions act as ionic cross-linkers of the carboxylic groups, providing rigid networks with much higher Tg, and storage and loss moduli. This explains that despite sorbing similar amounts of water to carbopol, the changes on the mechanical properties of noveon compacts were much less important (i.e., G' and G" decreased up to one order of magnitude).

Microviscosity of hydroxypropylcellulose gels as a basis for prediction of drug diffusion rates.

This study investigated the influence of the rheological properties of hydroxypropylcellulose (HPC) gels on the in vitro release of theophylline included in the gel at 0.2 g/l. Experiments were performed with six HPC varieties (mean molecular weight between 5x105 and 1.2x106, nominal viscosity between 100 and 4000 mPa.s) at concentrations of 0-2% (w/w). Theophylline diffusion coefficients at 37 degrees C ranged from 3.5x10-7 to 1.1x10-3 cm2/min, and were in all cases markedly higher than those predicted on the basis of gel macroviscosity as determined by capillary viscometry. In general, the theophylline diffusion coefficient declined exponentially with HPC concentration; in the case of the lowest-molecular-weight HPC, however, the diffusion coefficient remained constant to HPC concentrations of up to 0.8%, probably because of the high entanglement concentration of the HPC. Gel microviscosities as determined by dynamic light scattering (DLS) with latex microspheres (162 nm diameter) were considerably lower than the macroviscosities determined by capillary viscometry, and similar to microviscosities estimated on the basis of theophylline diffusion. Nevertheless, macroviscosity was correlated with microviscosity, suggesting that it is of value for approximate estimates of rates of diffusion of theophylline from HPC gels.

Degradation of hydroxypropylcellulose by Rhizomucor: effects on release from theophylline-hydroxypropylcellulose tablets.

The stability of several varieties of hydroxypropylcellulose was monitored during 3 years of storage (1) under the conditions recommended by manufacturers and official pharmacopoeias (simple storage in closed containers) and (2) at zero relative humidity. After 1 year, severe degradation of the varieties with lower initial pH and particle size stored at ambient relative humidity was shown by changes in their molecular weight and in the pH and apparent viscosity of 2% aqueous dispersions. Microbiological analyses showed the observed degradation to be attributable to the action of fungi of the genus Rhizomucor. The changes in apparent viscosity significantly affected the release of theophylline from direct compression tablets formulated with the degraded excipients.

Evaluation of low-substituted hydroxypropylcelluloses (L-HPCs) as filler-binders for direct compression.

The aims of this study were to assess the potential value of low-substituted hydroxypropylcelluloses (L-HPCs) as excipients of direct compression, and to investigate relationships between the chemical and physical properties of the polymers and (a) the powder rheological behavior and (b) drug release profiles from direct compressed tablets elaborated with (1:1) theophylline:L-HPC mixtures. Experiments were performed with five L-HPC varieties of different nominal particle sizes and degree of substitution. The products were characterized with regard to the moisture content, density, IR and Raman spectroscopy, hydroxypropyloxy content, heat of hydration, particle size, specific surface and porosity, and important differences were found in relation with all these properties. The differences in specific surface principally determine the flow and compaction properties of the powders, and the mechanical and microstructural properties of the tablets. The control of the hydroxypropyloxy content and the particle size of the L-HPCs allow the theophylline release profile to be regulated.

A comparison of gas-liquid chromatography, NMR spectroscopy and Raman spectroscopy for determination of the substituent content of general non-ionic cellulose ethers.

This paper describes and compares three techniques that can be used to characterize the substituent content of hydroxypropylcellulose (HPC and L-HPC) and hydroxypropyl methylcellulose (HPMC): gas-liquid chromatography (GLC) with a BP1 column and FI detection, 13C-NMR spectroscopy of hydrolysed samples, and Raman spectroscopy. GLC and 13C-NMR spectroscopy both allow independent quantification of hydroxypropoxyl and methoxyl contents. 13C-NMR spectroscopy, though requiring lengthier sample preparation, has the advantage of also quantifying the degree of substitution at each substitutable glucopyranose hydroxyl. Raman spectroscopy may be useful for rapid approximate estimation of hydroxypropoxyl content.

Use of the crushing strength parameter for quality control of phenobarbital-microcrystalline cellulose tablets.

Three variables of the tablet manufacturing process (duration of mixing with lubricant, maximum compression force and compression rate) were studied for their effects on various properties of direct compression phenobarbital-microcrystalline cellulose tablets. Mixing time and maximum compression force were found to have a marked influence on friability and dissolution rate; crushing strength was found to be a useful parameter for quality control.

Nifedipine/atenolol interactions in gastrointestinal absorption and biotransformation.

The combination of nifedipine and atenolol is widely used for the treatment of hypertension. In the present study, experiments performed in rats indicated that neither drug affects the gastric or intestinal absorption of the other. In assays of the biotransformation of nifedipine in liver homogenates, breakdown was much more rapid in homogenates from male rats than from female rats. In the presence of atenolol, the breakdown rate was significantly increased in homogenates from male rats, and significantly reduced in homogenates from female rats.

Hydration and N-acetyl-l-cysteine alter the microstructure of human nail and bovine hoof: implications for drug delivery.

This work aimed to (a) characterize the microstructure and porosity of human nail and bovine hoof by mercury intrusion porosimetry and SEM image analysis, (b) study the effects of hydration and of N-acetyl-l-cysteine treatment on the microstructure of both membranes, and (c) determine whether the microstructural modifications were associated with changes in drug penetration measured by standard diffusion studies. Bovine hoof surface is more porous than nail surface although there were no differences between the mean surface pore sizes. Hydration and N-acetyl-l-cysteine increased the roughness and apparent surface porosity, and the porosity determined by mercury intrusion porosimetry of both membranes. Pore-Cor™ was used to generate tridimensional structures having percolation characteristics comparable to nail and hooves. The modeled structures were horizontally banded having an inner less-porous area which disappeared upon treatment. Treatment increased the predicted permeability of the simulated structures. Triamcinolone permeation increased significantly for hooves treated N-acetyl-l-cysteine, i.e., the membranes for which microstructural and permeability changes were the largest. Thus, microstructural changes determined via mercury intrusion porosimetry and subsequently modeled by Pore-Cor™ were related to drug diffusion. Further refinement of the technique will allow fast screening of penetration enhancers to be used in ungual drug delivery.

Interfacial adsorption of polymers and surfactants: implications for the properties of disperse systems of pharmaceutical interest.

This review considers basic aspects of the interfacial adsorption of polymers and surfactants, with particular reference to the relevance of these processes for the formulation of pharmaceutical disperse systems. First, we discuss different approaches to the interpretation of adsorption isotherms, paying particular attention to systems containing more than one adsorbate. Second, we consider the implications of adsorption for the properties of suspensions, emulsions, and colloidal systems, particularly as regards the use of polymers and surfactants for stabilizing disperse systems, for controlling flocculation, and for modifying the biopharmaceutical behavior of colloidal drug carriers. Finally, we present a number of representative examples of the importance of adsorption of macromolecules in pharmaceutical systems.

Effect of microcrystalline cellulose grade and process variables on pellets prepared by extrusion-spheronization.

This study evaluated the effects of spheronizer load and speed on the size, circularity, microporosity, compressibility, and friability of pellets prepared by extrusion-spheronization of wet microcrystalline cellulose (MCC) masses with a water content shown by mixer torque rheometry to ensure maximum consistency. Two MCC grades with different mean particle size were used. Both gave pellets with good particle size, sphericity, and compressibility, under a wide range of spheronization conditions. Modification of pellet properties of interest (including size and porosity) was possible by adjustment of spheronization conditions and MCC grade; in particular, pellet porosity was greater with MCC of larger particle size.

The stability of theophylline tablets with a hydroxypropylcellulose matrix.

The behavior of 40:60 anhydrous theophylline/hydroxypropylcellulose (HPC) direct compression tablets obtained using a variety of hydroxypropylcelluloses with low or medium-high degrees of substitution (L-HPCs and HPCs, respectively) was determined immediately following their preparation and after storage for 6 months at 20 degrees C and a relative humidity (RH) of either 70.4% or 93.9%. The lower relative humidity did not bring about hydration of the active principle in any formulation, but the higher relative humidity totally hydrated the drug in all except one L-HPC formulation, in which hydration remained incomplete. Both relative humidities caused significant tablet swelling, with L-HPC formulations being more affected than HPC formulations. Drug release was slowed by hydration of the active principle, but accelerated with tablet swelling. The lower relative humidity caused significant alteration of drug release characteristics in only two L-HPC formulations, release from which was accelerated, while the higher relative humidities only failed to cause such alterations in two HPC formulations, with release from all except one of the others slowed (in the exceptional formulation, which exhibited incompletely hydrated theophylline and the greatest swelling of all, release was accelerated).

A comparison of cellactose with two ad hoc processed lactose-cellulose blends as direct compression excipients.

Three processed lactose-cellulose blends of similar composition, particle size and true density were compared as direct compression excipients: one was prepared by dry granulation, one by extrusion-spheronization, and the commercial product Cellactose. Differences among their flow properties depended solely on their different sphericities. Unlike those of the other blends, Cellactose particles exhibited numerous macropores. The mean yield pressures of all three blends were similar to those of direct compression lactoses. Cellactose tablets prepared at a punch pressure that largely eliminated macropores (pores >1 microm) had better mechanical properties but much poorer disintegration than tablets of the other blends prepared at the same punch pressure. However, the tensile strength and disintegration time of Cellactose tablets both fell rapidly as macropore volume was increased by reducing punch pressure, while the enthalpy of wetting/dissolution rose. The strength and water-resistance of well-compacted Cellactose tablets is attributed to the spatial distribution of lactose and cellulose in Cellactose particles, rather than to beta-lactose content or extra-particular structural features.

Development of tablets for controlled joint release of nifedipine and atenolol.

Oral combinations of nifedipine and atenolol are widely used in the treatment of hypertension, proving particularly effective when the atenolol is released immediately and the nifedipine is released in a sustained manner. This work examined the potential of combining nifedipine and atenolol in a tablet, which would be easier to manufacture than currently available combined formulations. The results indicated that a 40:60 (w/w) nifedipine-atenolol mixture forms a eutectic melting at 140 degrees C. Nevertheless, both drugs were stable when incorporated in tablets elaborated using cellulose ethers as base excipients. Tablets prepared from atenolol-lactose granules and solid dispersions of nifedipine-hydroxypropylmethylcellulose (100 cP) had more adequate dissolution profiles than a more complex reference formulation in hard capsules.

Extrusion-Spheronization of blends of carbopol 934 and microcrystalline cellulose.

We evaluated the effects of several process variables on the pharmaceutical and drug release properties of extrusion-spheronization pellets of blends of Carbopol 934 and microcrystalline cellulose (MCC) containing a high proportion of Carbopol. The model drug was theophylline. Rheological monitoring during mixing was by mixer torque rheometry. Carbopol:MCC blends wetted with a CaCl2 solution showed different rheological behavior compared to blends with a high proportion of MCC wetted with water only. In contrast to previous suggestions, the optimal wetting point for extrusion did not coincide with the point of peak torque, but occurred just beyond this point, at much lower torque. The influence of process variables on blend properties was investigated with a three-variable factorial design (Carbopol:MCC ratio, wetting liquid proportion, CaCl2:Carbopol ratio), and the influence of process variables on pellet properties with a four-variable design (the variables listed plus extrusion screen hole diameter). Blend torque values were strongly influenced by CaCl2 proportion, while mean pellet diameter was influenced by Carbopol:MCC ratio. Mean pellet diameter also differed depending on whether the pellets contained theophylline. The observed among-formulation differences in theophylline release kinetics were largely explained by differences in pellet size and theophylline hydration state. Compaction of pellets to form tablets markedly modified the drug release profile, making it biphasic.